Synthetic porphyrins and metalloporphyrins have become increasingly important in numerous and diverse technical fields. Their several practical applications include their use as sensitizers in photodynamic therapy (PDT) (Mody, (2000) J. Porphyrins Phthalocyanines 4: 362); in electron transfer (Lippard and Berg, (1994) Principles of Bioinorganic Chemistry, University Science Book: Mill Valley, Calif.); in DNA strand cleavage (Bennett et al., (2000) Proc. Natl. Acad. Sci. 97: 9476; Hashimoto et al., (1983) Tetrahedron Letters, 24: 1523); as carriers of cytotoxic anticancer drugs such as platinum (Song et al., (2002) Inorganic Biochemistry 83: 83; and Lottner et al., (2002) J. Med. Chem., 45, 2064); as components of synthetic receptors (Jain and Hamilton, (2002) Org. Lett. 2: 1721); and as oxidation catalysts (Guo et al., (2001) J. Mol. Catal. A Chem. 170: 43). Additionally, functionalized porphyrins have become important leads in current drug discovery techniques (See Mody, supra, and Priola et al., (2002) Science 287: 1503). Accordingly, the development of new methodologies and strategies to improve the synthesis of functionalized porphyrins has become highly desirable.
Numerous methods for the synthesis of porphyrins are known. The classical methods for porphyrin synthesis typically require harsh reaction conditions and can provide disappointingly low yields (Rothemund, (1935) J. Am. Chem. Soc., 57: 2010; Adler et al., (1967) J. Org. Chem. 32: 476). Newer methodologies, such as those developed by Lindsey and colleagues, have resolved certain issues regarding reaction conditions and yields (Lindsey et al., (1987) J. Org. Chem. 52: 827). More recently, transition metal-catalyzed organic synthesis methodologies (e.g., Suzuki coupling, Heck-type coupling, and Stille cross coupling), have been successfully employed with porphyrin systems, providing versatile and general synthetic approaches for the preparation of a variety of functionalized porphyrins and porphyrin analogs. See, e.g., DiMagno et al., (1993) J. Org. Chem., 58: 5983; DiMagno et al., (1993) J. Am. Chem. Soc. 115: 2513; Chan et al., (1995) Tetrahedron 51: 3129; Zhou et al., (1996) J. Org. Chem. 61: 3590; Risch and Rainer, (1997) Tetrahedron Letters 38: 223; Hyslop et al., (1998) J. Am. Chem. Soc. 120:12676; Boyle and Shi, (2002) J. Chem. Soc. Perkin Trans., 1: 1397; and Pereira et al., (2002) J. Chem. Soc. Perkin Trans., 2: 1583. See also, Suzuki, (1998) Metal-Catalyzed Cross-Couplinq Reactions, pp. 49-97, Wiley-VCH, Weinheim, Germany; Liu et al., (1998) J. Chem. Soc., Dalton Trans. 1805; Shi et al., (2000) J. Org. Chem. 65: 1650; Shanmugathasan et al., (2000) Porphyrins Phthalocyanines 4: 228; Lovine et al., (2000) J. Am. Chem. Soc. 122: 8717; Deng et al., (2000) Angew. Chem. Int. Ed. 39: 1066; and Chang et al., (2003) J. Org. Chem. 68: 4075; U.S. Pat. No. 5,550,236 and U.S. Pat. No. 5,756,804, which references are incorporated herein by reference. Further, porphyrin synthesis via palladium-catalyzed C—N bond formation, see Khan et al., (2001) Tetrahedron Lett. 42: 1615; Takanami et al., (2003) Tetrahedron Lett. 44: 7353, and metal-mediated C—C bond formation, see Sharman et al., (2000) Porphyr. Phthalocyanines 4: 441, has been reported.
Each of these foregoing methods, however, possesses undesirable aspects that should be mitigated, including incompatibilities between catalysts and reaction compounds, low turnover number (TON) and low turnover frequency (TOF). Thus, despite recent advances in porphyrin chemistry, a need still exists for facile and general syntheses for, in particular, heteroatom-substituted porphyrins and metalloporphyrins.
More particularly, a need exists for facile and general syntheses for heteroatom-substituted chiral porphyrins. Chiral porphyrins have found a range of applications in many areas, such as asymmetric catalysis, chiral recognition/sensing, and enzymatic mimicry. Of particular interest is the use of chiral porphyrins in asymmetric catalysis.
Biologically relevant porphyrins are among the most versatile ligands for transition metal complexes. See Brothers, (2001) Adv. Organometallic Chem. 46:223; Brothers, (2001) Adv. Organometallic Chem. 48: 289. Metalloporphyrins have found a diverse array of applications in areas ranging from chemistry to biology and from materials to medicine. Metalloporphyrins are known to catalyze a range of fundamentally and practically important chemical transformations, including an array of atom/group transfer reactions, such as oxene (epoxidation and hydroxylation), nitrene (aziridination and amination), and carbene (cyclopropanation and carbene insertion) transfers, that allow the direct conversion of abundant and inexpensive alkenes and alkanes into functional molecules. See The Porphyrin Handbook; Kadish, K. M., Smith, K. M., Guilard, R., Eds., Academic Press: San Diego, 2000-2003; Metalloporphyrins in Catalytic Oxidations; Sheldon, R. A., Ed.; Marcel Dekker: New York, 1994; Metalloporphyrins Catalyzed Oxidations: Montanari, F., Casella, L., Eds., Kluwer Academic Publishers: Boston, 1994. Due to the unique ligand environment and metal coordination mode of metalloporphyrins, unusual reaction selectivities and excellent catalyst turnovers have been observed for metalloporphyrin-based catalysts. Thus, there is a significant interest in designing and synthesizing chiral porphyrins for developing asymmetric versions of the abovementioned catalytic processes.
Since the first application of a chiral iron porphyrin complex for catalytic asymmetric epoxidation, see Groves et al., (1983) J. Am. Chem. Soc. 105: 5791, a number of chiral porphyrins have been synthesized as potential asymmetric catalysts. See Marchon, (2003) in The Porphyrin Handbook; supra, Vol. 11, pp 75-132; Simonneaux et al., (2002) Coord. Chem. Rev. 228: 43; Rose et al., (2000) Polyhedron 19: 581; Collman et al., (1999) Chemtracts 12: 299; Rose et al., (1998) Coord. Chem. Rev. 178-180: 1407; Collman et al., (1993) Science 261: 1404; Rose et al., (2004) Chem. Eur. J. 10: 224. Although significant progress has been made in this area, catalytic reactions based on metalloporphyrins have not been developed into practical methodologies that can be used in asymmetric synthesis. This lack of development can be attributed mainly to the expense and difficulty associated with chiral porphyrin synthesis.
Several approaches have been applied to chiral porphyrin synthesis. See Marchon, supra, Rose et al., (2000), supra, and Collman et al., (1993), supra. The most general and chirally economic scheme for synthesizing chiral porphyrins is to covalently attach suitable chiral building blocks to a preformed porphyrin synthon comprising peripheral functional groups. See Tani et al., (2002) Coord. Chem. Rev. 226: 219; Simonneaux et al., supra; Collman et al., (1999), supra; Rose et al., (1998), supra; Boschi, in Metalloporphyrins Catalyzed Oxidations: Montanari, F., Casella, L., Eds., Kluwer Academic Publishers: Boston, 1994; pp 239-267; and Naruta, (1994) in Metalloporphyrins in Catalytic Oxidations; Sheldon, R. A., Ed.; Marcel Dekker: New York, pp 241-259.
Representative porphyrin synthons that have been found to be useful for synthesizing chiral porphyrins include meso-tetrakis(o-aminophenyl)porphyrin (See Collman et al., (1975) J. Am. Chem. Soc. 97: 1427 and Leondiadis et al., (1989) J. Org. Chem. 54: 6135), meso-tetrakis(2,6-diaminophenyl)porphyrin (see Rose et al., (1996) J. Am. Chem. Soc. 118: 1567), meso-tetrakis (2,6-dihydroxyphenyl)porphyrin (see Collman et al., (1997) Inorg. Synth. 31: 117 and Tsuchida et al., (1990) J. Chem. Soc.-Dalton Trans. 2713), and meso-tetrakis(2,6-dicarboxyphenyl)porphyrin (ee Nakagawa et al., (2001) Org. Lett. 3: 1805). These synthons allow the attachment of chiral acids, chiral amines, or chiral alcohols through amide or ester bond formation. To enhance the synthetic utility and flexibility of metalloporphyrin-based asymmetric catalysis, it is desirable to develop alternative synthons for the versatile construction of chiral porphyrins that could be employed in practical asymmetric catalysis.
Within this context, halogenated porphyrins, e.g., bromoporphyrins, have been shown to be versatile precursors for the synthesis of heteroatom-functionalized porphyrins via metal-catalyzed carbon-heteroatom cross-coupling reactions with soft, non-organometallic nucleophiles. See Chen et al., (2003) J. Org. Chem. 68: 4432; Gao et al., (2003) J. Org. Chem. 68: 6215; Gao et al., (2003) Org. Lett. 5: 3261; and Gao et al., (2004) Org. Lett. 6: 1837. These methods are based on metal-catalyzed carbon-heteroatom bond formations. See Lev et al., (2003) Angew. Chem.-Int. Edit. 42: 5400; Prim et al., (2002) Tetrahedron, 58: 2041; Muci et al., (2002) Top. Curr. Chem. 219: 131; Hartwig, (2002) in Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley-Interscience: New York, pp 1051; Yang et al., (1999) J. Organomet. Chem. 576: 125; Wolfe et al., (1998) Acc. Chem. Res. 31: 805; Hartwig, (1998) Angew. Chem.-Int. Edit. 37: 2047; and Hartwig, (1997) Synlett, 329. Such syntheses can be performed under mild conditions with a wide range of nucleophiles, including amines, amides, alcohols, and thiols, leading to a family of novel porphyrins comprising otherwise inaccessible heteroatom functionalities in high yields.
For example, a general and efficient method has been developed for the synthesis of meso-arylamino- and meso-alkylamino-substituted porphyrins from reactions of meso-bromoporphyrins with amines. See Chen et al., (2003) J. Org. Chem. 68: 4432. Similar methodology also can be effectively applied to brominated diphenylporphyrins and tetraphenylporphyrins, leading to the versatile synthesis of porphyrin derivatives bearing multiple arylamino and alkylamino groups. See Gao et al., (2003) J. Org. Chem. 68: 6215. In addition, a convenient and general approach has been developed for the synthesis of meso-aryloxy- and meso-alkoxy-substituted porphyrins from reactions with alcohols via palladium-catalyzed etheration. See Gao et al., (2003) Org. Lett. 5: 3261. A general synthetic method for meso-amidoporphyrins from reactions with amides via palladium-catalyzed amidation also has been developed. See Gao et al., (2004) Org. Lett. 6: 1837. Expanding the synthetic strategy to palladium-mediated carbon-sulfur bond formation, a versatile procedure also has been developed for the synthesis of meso-arylsulfanyl- and mesoalkylsulfanyl-substituted porphyrins from reactions of the corresponding bromoporphyrin precursors and thiols. See Gao et al., (2004), submitted for publication. There exists, however, a need in the art for improved methods for the synthesis of heteroatom-substituted chiral porphyrins.
Accordingly, the presently disclosed subject matter describes the use of haloporphyrins as a new class of synthons for the versatile syntheses of chiral porphyrins via metal catalyst-mediated carbon-heteroatom bond formation reactions with chiral nucleophiles, such as chiral amines, chiral amides, chiral alcohols, and chiral thiols, and the use of these chiral porphyrins as catalysts in asymmetric cyclopropanation, asymmetric aziridination, and asymmetric epoxidation reactions.